Physiologically active substances such as various hormones, neurotransmitters, etc. regulate the biological function via specific receptor proteins present on cell membranes. Many of these receptor proteins are coupled with a guanine nucleotide-binding protein (hereinafter sometimes simply referred to as G protein) and mediate the intracellular signal transduction via activation of G protein. These receptor proteins possess the common structure containing seven transmembrane domains and are thus collectively referred to as G protein-coupled receptor proteins (GPCR) or seven-transmembrane receptor proteins (7TMR).
G protein-coupled receptor proteins are present on the cell surface of each functional cell and organ in the body, and play important physiological roles as the target of the molecules that regulate the functions of these cells and organs, e.g., hormones, neurotransmitters, physiologically active substances and the like. Receptors transmit signals to cells via binding with physiologically active substances, and the signals induce various reactions such as activation and inhibition of the cells.
To clarify the relationship between substances that regulate complex biological functions in various cells and organs in the body, and their specific receptor proteins, in particular, G protein-coupled receptor proteins would elucidate the functional mechanisms in various cells and organs in the body to provide a very important means for development of drugs closely associated with these functions.
For example, in various organs in the body, their physiological functions are controlled through regulation by many hormones, hormone-like substances, neurotransmitters or physiologically active substances. In particular, physiologically active substances are found in numerous sites of the body and regulate the physiological functions through their corresponding receptor proteins. Many unknown hormones, neurotransmitters or many other physiologically active substances still exist in the body and, as to their receptor proteins, many of these proteins have not yet been reported. In addition, it is still unknown if there are subtypes of known receptor proteins.
It is a very important means for development of drugs to clarify the relationship between substances that regulate complex functions in vivo and their specific receptor proteins. Furthermore, for efficient screening of agonists and antagonists to receptor proteins in development of drugs, it is required to clarify functions of genes for these receptor proteins expressed in vivo and express the genes in an appropriate expression system.
In these receptor proteins, receptor proteins in which the corresponding ligands including agonists and antagonists are yet unidentified are referred to as orphan receptor proteins. GPR17 is known as one of the orphan G protein-coupled receptor proteins. WO 94/12635 discloses only sequence information of GPR17. GB 2360586 discloses this protein as a leukotriene receptor but has no description of expression distribution therein and merely mentions that other known leukotriene receptor is expressed in the lung and thus available for the treatment or prevention of immune diseases such as COPD, allergic rhinitis, AIDS, rheumatism, psoriasis, atopic dermatitis, etc., and cardiovascular diseases. WO 2003/025138 describes GPR17 as one of genes whose expression is changed in cancer. WO 2003/07127 discloses a ligand screening assay using an orphan GPCR-GFP fusion protein, in which a GPR17-GFP fusion sequence is shown. In J. Neurochem., 70, 1357-1365 (1998), a variant with a 28-amino acid N-terminal extension is reported. This gene is cloned from human hippocampus and shown to be expressed in the brain. In J. Neurochem., 81, 575-588 (2002), rat GPR17 is reported to be expressed in the oligodendrocyte.
On the other hand, it is known in Acta Haematol., 1958, 19 (6): 321-326 that 5-aminolevulinic acid is a hem protein precursor, and the urine level of 5-aminolevulinic acid increases in the patient with lead poisoning to cause severe neuropathy as a result. It is described in Trends Biochem. Sci., 1998, 23, 217-221 that 5-aminolevulinic acid and porphobilinogen take part in lead poisoning.